A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development

Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3368-72. doi: 10.1073/pnas.90.8.3368.


The mammalian Y chromosome carries the SRY gene, which determines testis formation. Here we review data on individuals who are XX but exhibit male characteristics: some have SRY; others do not. We have analyzed three families containing more than one such individual and show that these individuals lack SRY. Pedigree analysis leads to the hypothesis that they carry recessive mutations (in a gene termed Z) that allow expression of male characteristics. We propose that wild-type Z product is a negative regulator of male sex determination and is functional in wild-type females. In males, SRY product represses or otherwise negatively regulates Z and thereby allows male sex determination. This hypothesis can also explain other types of sex reversal in mammals, in particular, XY females containing SRY. Some of these individuals may have mutations at the Z locus rendering them insensitive to SRY. Recessive mutations (such as the polled mutation of goats) leading to sex reversal are known in a variety of animals and might be used to map and ultimately clone the human Z gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Child
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Disorders of Sex Development* / genetics*
  • Female
  • Gene Expression Regulation*
  • Genes, Recessive
  • Genetic Carrier Screening
  • Homozygote
  • Humans
  • Male
  • Mammals
  • Models, Genetic*
  • Molecular Sequence Data
  • Nuclear Proteins*
  • Oligodeoxyribonucleotides
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction / methods
  • Sex Chromosome Aberrations*
  • Sex Determination Analysis*
  • Sex-Determining Region Y Protein
  • Transcription Factors*
  • X Chromosome*
  • Y Chromosome*


  • DNA-Binding Proteins
  • Nuclear Proteins
  • Oligodeoxyribonucleotides
  • SRY protein, human
  • Sex-Determining Region Y Protein
  • Transcription Factors